APOBEC3B expression is promoted by lincNMR collaborating with TGF-β-Smad pathway.

Kosuke Ota, Satoshi Sakai, Tatsuya Ohhata, Takahito Suzuki, Chiharu Uchida, Hiroyuki Niida, Masatoshi Kitagawa

Carcinogenesis 2023 May 15

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Long non-coding RNAs (lncRNAs) participate in carcinogenesis and cancer malignancies. Transforming growth factor-β (TGF-β) is involved in various cellular processes including cancer progression. We performed comprehensive RNA sequencing analyses to identify lncRNAs regulated by TGF-β and found that lincNMR (long intergenic noncoding RNA-nucleotide metabolism regulator, also identified as MAP3K9-DT) was induced by TGF-β in various cell lines. There are several variants of lincNMR (hereafter lincNMRs) in the lincNMR/MAP3K9-DT locus, and their expression was increased by TGF-β. TGF-β-mediated induction of lincNMRs was decreased by depletion of Smad2/3 in Huh7, suggesting that the TGF-β-Smad pathway is involved in lincNMRs expression. We also found that APOBEC3B but not other APOBEC family members were a target gene of lincNMRs. APOBEC3B, a cytidine deaminase, promotes C to U mutation and highly expressed in various human cancers. Although it is associated with cancer progression, regulatory mechanisms of APOBEC3B expression have not been fully elucidated. We performed RNA immunoprecipitation assays and proved that lincNMRs bound to endogenous Smad2 in Huh7 cells. The increased activity of the promoter of APOBEC3B induced by overexpression of Smad2/3 was inhibited by depletion of lincNMRs. These data suggest that lincNMRs participate in APOBEC3B expression by collaborating with TGF-β-Smad pathway. High expression of lincNMRs was positively correlated with high expression of APOBEC3B in various cancer cell lines. Overexpression of APOBEC3B as well as lincNMR was found in human cancers such as hepatic and lung cancers and was associated with their poor prognosis, suggesting that lincNMR may contribute to tumor malignancy via enhanced expression of APOBEC3B. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Citation

Kosuke Ota, Satoshi Sakai, Tatsuya Ohhata, Takahito Suzuki, Chiharu Uchida, Hiroyuki Niida, Masatoshi Kitagawa. APOBEC3B expression is promoted by lincNMR collaborating with TGF-β-Smad pathway. Carcinogenesis. 2023 May 15;44(1):1-14